Quaternary ammonium salts of basic derivatives of substituted cinnamic acids and methods of producing same



Patented F eb. 23, 1954 2,70,360 OFF o 'r p a AMMONIUM SALTS O-F BASIC DERIVATIVES or SUBSTITUTED om- NAMIC Aoms AND METHODS or PRODUC:

ING SAME William A. Lott, Maplewood, N. J., assignor to Mathieson Chemical Corporation, New York, N. Y a corporation of Virginia No -Drawing. Application November 30, 1951 Serial No. 2 5l, -l i[3v .8 Claims, I

Thi invention e e a and has r i o je t t pr vi ion f, certain qu erna vlamrsqe um alt f dinnami ci eri t v ifihe mmu sis emb ace b thi ,mve ti n com i e quat rn {Sa 9 th genformula wherein one B represents a member of-the class consisting of alkyl and aryl groups the other B, represents hydrogen, X represents a member of the class consisting of O, NH, and N(alkyl) groups, and Z represents a quaternary ammonium nitrogen. (The monocyclic aryl group may be unsubstituted or may besubstituted with a halo, alkyl, alkoxy, alkylene dioxy, and dialkyle emi oup.)

The compounds of this invention possess V3111? able therapeutic properties, especially ganglionic blocking activity. In addition, those compounds of the general formula (II);

[wherein one It represents an aryl group and the other It represents hydrogen, R1 and R2 each rep: resent a member of the class consisting of, alkyl, aryl,- and aralkyl groups, and R3 represents a member of the class consisting of alkyl, alkenyl, aryl and aralkyl groups] possess acetyl choline ant n zin act vity. Comp nd of ge er Formula II in which the R substituent is a higher allay; group are not only effective ganglionic blocking agents but also possess cationicgdetere gent and bactericidal properties.

The compounds of this invention are. prepared by the method which essentially comprises interacting a tertiary amine III of the general tormula (monocyclic ary1)-C=C-O OX(alkylene)N pg, wherein is an amino group, with a quaternizing agent.

Tertiary amines III which are utilizablefor the purposes of the invention include, inter aliaf M B-diethylaminoethyl a-ethylcinna-mate B-diethylaminoethyl a-isopropylcinnainate fi-diethylaminoethyl fi-amylcinnamate N- (fi-diethylamincethyl) -a-ethylcinnamamide N- (/S-diethylaminoethyl) -/3-l0utylcinnamamide 3 diethylaminoethyl a. phenyl .-.o chlorocirr-v nainate 13-diethylaminoethyl a. ethyl-p dimethylaminoe t nn a fl-dimethylaminoethyl a-ethyl-3Asdimethoxycin- Y namate T 'y-dimethylaminopropyl a-ethyl-methylenedioxye SA-cinnamate flflbenzyl-ethyl amino) ethyl a. hexylcinnamate dpdimethyl v diethylaminopropyl aphenylcinnamate fiadiethylaminoethyl li-decylfinnamate fi-diethylaminoethyl fi-propylcinnamate p-diethylaminoethyl B phenyl-p-methoxyoim namate N-ethyl-N diethylarninoethyl a-meth-ylcinnamamide N-(y-diethylaminopropyb -phenyl-p-methylcinnamamide B-dimethylaminopropyl fi phenylcinnamate N x iim th lam n9etbr .B q e er namamide N- (fl-diethylaminoethyl) ylaminocinnamamide N-(B diethylaminoethyl) wedecyl-p dirnethylraminocinnamamide p (phenyl-ethyl-ramino), ethyl @e hen lc h namate Tlfhe utili zable quaternizing agents include; dia kv s fates ea s e y Su ate a-llsrl 11 isle-S eeth l bromi e ethyl iQdidei r yl ha is es 9- b nzv ch o i e! e-ne th l mans chloride), esters (e. g. ethyl chloro icetate, methyl -t l e -sul n ts ethyl .sr m prqp nata n-oetyl iodoacetate), allgyl haloalkyl ethers .(e g. brp methqx bii n k allse yl al des ieoa lvl hlo ide he alk h los se l sil ers chloromethyl es zsr e hyl re rise): The following examples are illustrative of the invention:

- a-phenyl-p-dimeth- /3 phe ylcinnamido)cthyl l m tin monium bromide 3 (and. the ether removed), the residue is dissolved in 300 ml. benzyl alcohol and 30 grams of ethyl bromide. This solution is then heated at 100 C. for three days; at which time the solution is cooled and diluted with ether. The product is recrystallized from an alcohol-ether solution to give about 80 grams of a white crystalline material, M. P. about l66l68 C.

EXAMPLE 2- [p- (a-phenylcinndmido) ethyl] -trimethylammonium iodide Using 33.4 g. of N,N-dimethyl-ethylenediamine in place of N,N-diethyl-ethylenedianune, in Example l, the product N-(fl-dimethylaminoethyl) -a-phenylcinnamamide hydrochloride is obtained, M. P. about 140-141 C. This intermediate is similarly treated with alkali and heated with 43 g. of methyl iodide to yield a white crystalline material [,c-(a-phenylcinnamido) ethylltrimethylammonium iodide, M. P. about l80l81 C.

EXAMPLE 3 8 (a. phenylcz'nndmoyloxy)ethylldiethylmethylammonium bromide A solution of 30 grams li-(diethylaminoethyl) a-phenylcinnamate hydrochloride in 200 ml. of water is alkalinized with potassium carbonate and extracted with 275 ml. ether and dried. The ether is distilled oil and to the residue (19.6 g.) is added a solution of 16 g. of methyl bromide in 40 ml. alcohol. After three days of solution is diluted with 80 ml. ether and filtered. The product is recrystallized from 90 ml. methyl ethyl ketone to give about 14 g. of product melting at about 130-131 0.

EXAMPLE 4 [,8 (p-phenylcinndmido) ethyl] -trz'ethyldmmonium bromide 50 g. methyl p-phenylcinnamate and '70 g. N,N- diethylethylenediamine are refluxed together for twenty-four hours; and the excess amine removed under reduced pressure. The residue is taken up in 400 ml. ether and extracted with 5% hydrochloric acid. The acid extract is then washed with 100 ml. ether, alkalized with potassium carbonate; and the base obtained is extracted with ether, and dried. When the ether is distilled, there is obtained about 34 g. N-(fidiethylaminoethyl) c-phenylcinnamide. This material is dissolved in 200 ml. benzyl alcohol containing 120 g. ethyl bromide and heated at 60 C. for two days, and the solution is then diluted with 550 ml. ether. The product, filtered and recrystallized from 120 ml. methyl ethyl ketone, is [p-(B-phenylcinnamido)ethyl]triethylammonium bromide.

EXAMPLE 5 Using a molar equivalent of diethyl sulfate in place of ethyl bromide in Example 1, [5 (a phenylcinnamido)ethylltriethylammonium ethyl sulfate is obtained.

EXAMPLE 6 Using a molar equivalent of methyl p-toluenesulfonate in place of ethyl bromide in Example 1, [,3- (a-phenylcinnamido) ethyl] -diethylmethylammonium p-toluene-sulfonate is obtained.

4 EXAMPLE '7 Using a molar equivalent of benzyl bromide in place of ethyl bromide in Example 1, [fl-(aphenylcinnamido)ethyl] benzyldiethylammonium bromide is obtained.

EXAMPLE 8 [o (a decylcinnamz'do)ethylltriethylammonium bromide A solution of 27 g. of N-(fl-diethylaminoethyl) e-decylcinnamamide, B. P. l98-200 C./l mm., 100 ml. benzyl alcohol and 100 ml. ethyl bromide is allowed to stand at room temperature for three days. The benzyl alcohol is then removed under reduced pressure; and 100 m1. dry hexane is added. The hexane is also removed under reduced pressure and the procedure is repeated to yield a viscous residue. Anhydrous ether (200 ml.) is added and the residue crystallizes, yielding about 18 g. of solid product melting at about 99-100 C. After crystallization from hexane the melting point is about 99-100 0.

The following compounds are prepared in an analogous manner: l e-(a-decylcinnamoyloxy) ethyl] -triethylamrnonium bromide, a viscous liquid with the same solubility as the corresponding amide; [,c-(a-hexylcinnamido) ethyl] -triethylammonium bromide, M. P. about 137-139 C.; [B (a decylcinnamoyloxy)propyl] triethylammonium bromide, a viscous syrup; [5- (it-tetradecylcinnamido) ethyl] -triethylammonium bromide, M. P. about 93-94 C.

The invention may be embodied in various other ways within the scope of the appended claims.

I claim: 1. Compounds of the general formula (lower alkyl) (lower alkyl) fiH5CH=C-C OX(lower alkylene)-N (lower alkyl) (higher alkyl) (halo) References Cited in the file of this patent UNITED STATES PATENTS V Name Date Lott Dec. 13, 1938 Lott Feb. 16, 1943 OTHER REFERENCES Voigt et al.: Chem. Abstracts, vol. 36, page 6652 (1942).

Jensen et al.: Acta Chemica Scandanavica, 2, 381 (1948).

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1. COMPOUNDS OF THE GENERAL FORMULA 